Apomorphine is a selective dopamine receptor agonist that has been widely utilized as an emetic agent, sedative, antiparkinsonian agent and a behavior altering agent. Recent research and clinical studies have demonstrated that in males apomorphine has an erectogenic effect manifested by penile erection. The effect of apomorphine on female sexual functionality has not been previously investigated.
Females also can have sexual dysfunction that increases with age and is associated with the presence of vascular risk factors and onset of menopause. Some of the vascular and muscular mechanisms that contribute to penile erection in the male are believed to be similar vasculogenic factors in female genital response. It is known that in women, sexual arousal is accompanied by arterial inflow which engorges the vagina and increases vaginal lubrication and that the muscles in the perineum assist in achieving clitoral erection.
In the female, sexual dysfunction can arise from organic and psychogenic causes or from a combination of the foregoing. Female sexual dysfunction includes a failure to attain or maintain vaginal lubrication-swelling responses of sexual excitement until completion of the sexual activity. Organic female sexual dysfunction is known to be related in part to vasculogenic impairment resulting in inadequate blood flow, vaginal engorgement insufficiency and clitoral erection insufficiency.
Female sexual dysfunction has not been studied as extensively as male sexual dysfunction. This has partly been due to the difficulty of obtaining volunteer female subjects and to the historical belief that female sexual dysfunction was orgasmic-related (delayed or non-orgasmic) or libido and hence lacked an appropriate animal model.
The use of New Zealand White male rabbits as animal models for impotence has been well established. More recently, studies have reported that New Zealand White female rabbits are also suitable, relatively inexpensive animal models for studying the vascular pathology in female sexual dysfunction and have shown that vaginal engorgement and clitoral erection depend on blood inflow. See, for example, Park et al, "Vasculogenic female sexual dysfunction: the hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency," International Journal of Impotence Research, 9, (1), 27-37 (March 1997).
In medically managing vasculogenic sexual dysfunction, a female patient needs to have her discomfort or dysfunction reduced for sexual functioning. For psychogenic sexual dysfunction management, psychological sex therapy can also be employed to help the patient.
Apomorphine previously was shown to have very poor oral bioavailability. See, for example, Baldessarini et al., in Gessa et al., (eds.), Apomorphine and Other Dopaminomimetics, Basic Pharmacology, 1, 219-228, Raven Press, N.Y. (1981).
More recently, studies with males show that oral administration of apomorphine can be used to induce an erection in a psychogenic male patient, as long as the apomorphine dose required to achieve a significant erectile response is not accompanied by nausea and vomiting or other serious undesirable side effects such as arterial hypotension, flushing and diaphoresis. See U.S. Pat. No. 5,624,677 to El-Rashidy et al. and Heaton et al., Urology, 45, 200-206 (1995). The specific mechanisms by which apomorphine acts to produce an erectile response in a human patient are not yet completely understood but are believed to be centrally acting through dopamine receptor stimulation in the medial preoptic area of the brain.
It has now been found that certain controlled delivery systems for apomorphine can provide a practical therapeutic use in ameliorating sexual dysfunction in human females while reducing the likelihood of undesirable side effects.